US3450698A - Phenthiazine derivatives - Google Patents

Phenthiazine derivatives Download PDF

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US3450698A
US3450698A US505428A US3450698DA US3450698A US 3450698 A US3450698 A US 3450698A US 505428 A US505428 A US 505428A US 3450698D A US3450698D A US 3450698DA US 3450698 A US3450698 A US 3450698A
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methyl
phenthiazinyl
water
melting
washed
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Daniel Farge
Claude Jeanmart
Mayer Naoum Messer
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Rhone Poulenc SA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/18—[b, e]-condensed with two six-membered rings
    • C07D279/22—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom

Definitions

  • This invention relates to new therapeutically useful phenthiazine derivatives, to processes for their preparation and pharmaceutical compositions containing them.
  • R represents a hydrogen atom or a methyl group
  • R represents a hydrogen atom or a methyl or ethyl group
  • Y represents a hydrogen or halogen atom, or an alkyl, alkoxy or alkylthio group having 1 to 4 carbon atoms
  • R representing a methyl group when R and Y both represent hydrogen atoms, and salts thereof, for example alkali metal, alkaline earth metal, ammonium and amine salts.
  • the new phenthiazine compounds possess useful pharmacodynamic properties; in particular, they are particularly useful as. anti-inflammation and anti-rheumatic agents and have given good results as such in physiological experiments witiianimals when used in doses of to 100 mg.
  • R and R each represent a hydrogen atom or a methyl group and Y is as herein'before defined and, more particularly, (10- methyl 3 phenthiazinyl)acetic acid, (7 methoxy-lO- methyl 3 phenthiazinyl)acetic acid, 2 (10 methyl-3- phenthiazinyl)propionic acid and 2 (7. methoxy 10- methyl-3-phenthiazinyl)propionic acid.
  • the phenthiazine derivatives of Formula -I are prepared by the process which comprises subjecting a 3-acetylphenthiazine of the formula:
  • the 3-acetylphenthiazine starting materials of Formula II, in which R represents a hydrogen atom, can be prepared by hydrolyzing 3,lO-diacetylphenthiazines of the formula:
  • the 3,lO-diacetylphenthiazines of Formula IV can be prepared from phenthiazine derivatives of the formula:
  • phenthiazine derivatives of Formula V can be prepared by acetylation by methods known per se of phenthiazines of the formula:
  • the 3-acetylphenthiazine starting materials of Formula II, in which R represents a methyl group can be prepared by reacting a reactive ester of the Formula Z-CH (wherein Z represents the acid residue of a reactive ester such as a halogen atom or a sulphuric, for example methoxysulphonyloxy, or sulphonic, for example methanesulphonyloxy or toluene-p-sulphonyloxy, residue) with a phenthiazine of the formula:
  • ⁇ N/ COCHa H VII (wherein Y is as hereinbefore defined) itself obtained by hydrolysis of a 3,1'0-diacetylphenthiazine of Formula IV as aforementioned, or by the application of any other known method for preparing 3-substituted-phenthiazines such as the cyclisation of a 2-amino-4 acetyl-2'-bromodiphenylsulphide carrying in the 5'-position a substituent Y as hereinbefore defined.
  • the reaction between the ester of Formula ZCH and the phenthiazine of Formula VII is preferably carried out by heating the reactants in an organic solvent such as a lower alkanol.
  • the phenthiazine derivatives of Formula I are prepared by the process which comprises hydrolyzing and simultaneously decarboxylating a phenthiazine compound of the general formula:
  • reaction can be carried out by usual methods for the alkylation of malonic esters, i.e. by operating in the presence of a basic condensing agent such as an alkali metal alkoxide, alkali metal amide, or alkali metal, in an organic solvent such as benzene, toluene, ethanol or diethyl ether.
  • a basic condensing agent such as an alkali metal alkoxide, alkali metal amide, or alkali metal
  • phenthiazinylmalonates of Formula IX can be prepared from phenthiazine derivatives of the formula:
  • the phenthiazine derivatives of Formula X can be prepared by esterification of phenthiazine derivatives of Formula I in which R represents a hydrogen atom.
  • the phenthiazine derivatives of Formula I are prepared by hydrolyzing by methods known per se a phenthiazine of the general formula:
  • R, R and Y are as hereinbefore defined and T represents a radical known to be capable of conversion to a carboxy group by hydrolysis, such as a lower alkoxycarbonyl group, cyano, or a carbamoyl group.
  • the hydrolysis is carried out under the usual conditions for the preparation of acids by hydrolysis of such precursor groups, in acid or alkaline medium as appropriate.
  • the phenthiazine starting materials of Formula XI can be prepared by the following methods:
  • Hal represents a halogen, preferably chlorine or bromine, atom, and Y, R and T are as hereinbefore defined.
  • the amines of Formulae XV and XXI are prepared by reduction of the corresponding nitro derivatives of Formulae XIV and XX, respectively, by methods known per se, for example by catalytic reduction in the presence of palladium, or by hydrogenation using chemical reagents such as iron and acetic acid.
  • the azides of Formulae XVI and XXII are prepared by transformation of amines of Formulae XV and XXI, respectively, into their corresponding diazonium salts by methods known per se, followed by the action of sodium azide on the salts in water at a temperature of about 0 C.
  • the phenthiazine derivatives of Formula XVII are prepared by cyclisation of azides of Formulae XVI and XXII in a saturated hydrocarbon of high boiling point, such as Decalin, at a temperature between 100 and 200 C.
  • phenthiazine starting materials of Formula XVII can be obtained, in addition to the methods heretofore described, by the method described by S. P. Massie et coll., J. Org. Chem., 21, 1006 (1956) for the preparation of methyl (3-phenthiazinyl)acetate.
  • the alcohols of Formula XXIV are prepared from the esters of Formula XXIII by methods known per se for the conversion of esters to alcohols, in particular by means of lithium aluminium hydride.
  • halogenomethyl compounds of Formula XXV are prepared from the alcohols of Formula XXIV, for example, by the action of a phosphorus halide.
  • the nitriles of Formula XXVI are prepared by the action of a metallic cyanide, in particular sodium cyanide, on the halogenomethyl compounds of Formula XXV.
  • esters of Formula XXIII can be obtained, for example, by the method described by G. Cauquil and A. Casadevall, Bull. Soc. Chim., p. 768 (1955) for the preparation of 3-methoxycarbonyl-IO-methylphenthiazine.
  • the new phenthiazine derivatives of general Formula I can be converted into metal salts or addition salts with nitrogenous bases by application of methods known per se.
  • these salts can be obtained by the action of an alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal base, ammonia or an amine, on a phenthiazine of Formula I in an appropriate solvent such as alcohol, an ether, a ketone, or water; the salt formed is precipitated, if necessary after concentration of the solution, and is separated by filtration or decantation.
  • phenthiazine derivatives of Formula I are employed as such or in the form of pharmaceutically-acceptable salts, i.e. salts which are relatively innocuous to the animal organism in therapeutic doses of the salts, such as alkali metal, alkaline earth metal, ammonium and amine salts.
  • the 3-acetyl-IO-methylphenthiazine used as starting material is prepared according to G. Cauquil and A. Casadevall, Bull. Soc. Chim., p. 768 (1955 EXAMPLE II
  • a mixture of 3-acetyl-7-methoxy-IO-methylphenthiazine (28.5 g.), sulphur (5.12 g.) and morpholine (60 cc.) is heated under reflux for 16% hours.
  • the reaction mixture is then poured into ethanol (450 cc.).
  • the crystals produced are separated by filtration and washed with ethanol (45 cc.) and then with petroleum ether (100 cc.) to give (7-methoxy-10-methyl-3-phenthiazinyl)acetothiomorpholide (34 g.) melting at 142.
  • the 3-acetyl 7 methoxy-lO-methylphenthiazine employed as starting material is prepared by heating a mixture of 3-acetyl-7-methoxyphenthiazine (138.5 g.), methyl iodide (277 cc.) and methanol (692.5 cc.) in a sealed tube at 100 for 24 hours.
  • the reaction mixture is concentrated to dryness under a pressure of 20 mm. Hg, and the crystalline residue obtained is taken up in methylene chloride (700 cc.) and then in ethyl acetate (900 cc.).
  • the two organic solutions obtained are washed separately with water (500 cc.), then with an aqueous solution of sodium hyposulphite (200 g./litre; 500 cc.) and finally with water (250 cc.).
  • the two solutions are then dried separately over anhydrous sodium sulphate and treated with decolorising charcoal 15 g.).
  • the solutions are combined and then concentrated under reduced pressure (20 mm. Hg) to give 3-acetyl-7-methoxy-IO-methylphenthiazine (146 g.) melting at 125.
  • 3-acetyl-7-methoxyphenthiazine is obtained by heating a mixture of 2-amino-4-acetyl-2-bromo-S-methoxy-diphenylsulphide (158 g.), potassium carbonate (68 g.), copper powder (5.68 g.) and dimethylformamide (1200 cc.) under reflux for 22 hours.
  • the solution obtained is filtered and chromatographed over alumina (1200 g.). Elution is effected with dimethylformamide and there is recovered a fraction of 2720 cc. volume. This fraction is evaporated to dryness under reduced pressure (20 mm. Hg) and the crystalline residue is taken up in chloroform (90 cc.).
  • 2-amino-4-acetyl-2-bromo-5-methoxy-diphenylsulphide is prepared by introducing iron (223 g.) in small portions into a mixture of 2-nitro-4-acetyl-2-bromo-5'- rnethoxy-diphenylsulphide (320 g.), acetic acid (2800 cc.) and water (280 cc.) heated under reflux. Reflux is then continued for 2 hours minutes and the reaction mixture then concentrated to dryness under reduced pressure mm. Hg). The residue obtained is taken up in methylene chloride (1 litre) and water (3 litres).
  • the mixture is then filtered with the aid of a filtration adjuvant and washed with methylene chloride (500 cc.) and water (500 cc.).
  • methylene chloride 500 cc.
  • water 500 cc.
  • the organic solutions are combined, washed with water (1 litre) and treated wtih decolorising charcoal g.) and then dried over anhydrous sodium sulphate. After filtration and concentration to dryness under reduced pressure (20 mm. Hg), an oil (283.5 g.) is obtained which is taken up in diisopropyl ether (1100 cc.).
  • 2-nitro 4 acetyl 2' bromo-S'-methoxy-diphenylsulphide is prepared by pouring a solution of 85% potassium hydroxide (79.2 g.) in ethanol 370 cc.) at 60 into a solution of crude 2-bromo-5-methoxythiophenol (262 g.) in isopropanol (2390 cc.). 3-nitro-4-chloroacetophenone (239 g.) is then added to this reaction mixture and the mixture heated under reflux for 3 hours. The crystalline product is separated by filtration and washed with isopropanol (500 cc.).
  • the product obtained is dissolved in methylene chloride (2 litres), washed with water (1 litre), treated with decolorising charcoal (30 g.) and dried over anhydrous sodium sulphate. After filtration and concentration to dryness under a pressure of 20 mm. Hg, there is obtained a product (380 g.) melting at 130, which is recrystallised from acetonitrile (1600 cc.). The crystals are separated by filtration, washed with acetonitrile (250 cc.) and then with petroleum ether (750 cc.) to yield 2-nitro-4-acetyl-2-bromo-5-methoxy-diphenylsulphide (320 g.) melting at 135.
  • 3-nitro-4-chloroacetophenone can be prepared according to J. R. Keneford, J. Chem. Soc., p. 227 (1947).
  • the diazonium salt solution obtained is poured over a period of 85 minutes into a mixture of potassium ethylxanthate (307 g.), water (600 cc.) and ethyl aetate (2 litres) while maintaining the temperature at about After decantation, the mixture is extracted again with ethyl acetate (600 cc.), and the organic solutions combined, Washed with 4 N sodium hydroxide solution (250 cc.), water (1600 cc.), treated with decolorising charcoal (20 g.), dried over anhydrous sodium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm. Hg). A reddish-brown oil (415 g.) is obtained.
  • This oil is dissolved in ethanol (2250 cc.), and the solution is poured into a solution of potassium hydroxide (332 g.) in water (780 cc.), and the mixture heated under reflux for 10 hours. The mixture is then concentrated to dryness under reduced pressure (20 mm. Hg), the residue taken up in water (2 litres), and the solution obtained filtered in the presence of a filtration adjuvant and washed with water (300 cc.).
  • the extract is washed with water (100 cc.), dried over anhydrous sodium sulphate and then filtered and concentrated to dryness under a pressure of 20 mm. Hg.
  • 2-bromo-5- methoxythiophenol (262 g.) which in its crude oily state is employed for the condensation with 3-nitro-4-chloroacetophenone.
  • 3-amino-4-bromoanisole can be prepared according to H. H. Hodgson, J. Chem. 500., p. 946 (1935).
  • the 3-acetyl-7,IO-dimethylphenthiazine employed as starting material is prepared by heating a mixture of 3- acetyl-7-methylphenthiazine (14 g.), methyl iodide (28 cc.) and methanol (70 cc.) at 100 for 15 /2 hours.
  • the reaction mixture is concentrated to dryness under a pressure of 20 mm. Hg and the solid obtained is dissolved in methylene chloride cc.).
  • the solution obtained is washed with water cc.), then with 0.1 N sodium hyposulphite (100 cc.) and finally with water (150 cc.), treated with decolorising charcoal (2 g.), filtered and dried over anhydrous sodium sulphate. After filtration and concentration to dryness under reduced pressure (20 mm. Hg), there is obtained 3-acetyl-7,10-dimethylphenthiazine (12.9 g.) melting at 134.
  • 3-acetyl-7-met-hylphenthiazine is prepared by heating a mixture of 2-amino-4-acetyl-2-bromo-5-methyl-diphenylsulphide (32 g.), potassium carbonate (14.5 g.), copper powder (12 g.) and dimethylformamide (280 cc.) for 22 hours. The reaction mixture is then treated with decolorising charcoal (5 g.), filtered, and concentrated to dryness under reduced pressure (20 mm. Hg).
  • the crystalline residue is taken up in water (100 cc.) and the crystals separated by filtration to yield a product (36 g.) melting at This product is dissolved in dimethylformamide (100 cc.) and the solution obtained chromatographed over alumina (350 g.). After elution with dimethylformamide, there is recovered a fraction 1 litre in volume. This fraction is evaporated to dryness under reduced pressure (20 mm. Hg) and the crystalline residue is taken up in ethanol (50 cc.). The crystals are separated by filtration and washed with ethanol (30 cc.) and then with hexane (75 cc.). There is thus obtained 3-acetyl-7- methylphenthiazine (14 g.) melting at 189.
  • 2-amino 4 acetyl 2' bromo methyl-diphenylsulphide is prepared by introducing iron (30.8 g.) in small portions into a reaction mixture of 2-nitro-4-acetyl- 2-bromo-5'-methyl-diphenylsulphide (40.5 g.), acetic acid (350 cc.) and water (35 cc.) heated under reflux. Heating under reflux is continued for 2 hours and then the reaction mixture is concentrated to dryness under a pressure of 20 mm. Hg. The residue is taken up in water (500 cc.) and methylene chloride (200 cc.). The solution obtained is filtered in the presence of a filtration adjuvant, and Washed with methylene chloride 150 cc.).
  • 2-nitro 4 acetyl 2' bromo 5 methyl-diphenylsulphide is prepared by pouring a solution of 85% potassium hydroxide (9.9 g.) in ethanol (50 cc.) at 60 into a mixture of 2-bromo-5-methyl-thiophenol (30.5 g.), 3- nitro-4-chloro-acetophenone (30 g.) and isopropanol (300 cc.). The reaction mixture is heated under reflux for 3 hours, and then concentrated to dryness under a pressure of 20 mm. Hg.
  • 3-nitro-4chloro-acetophenone can be prepared accord ing to J. R. Keneford, J. Chem. Soc., p. 227 (1947).
  • 2-bromo-5-methyl-thiophenol can be prepared according to K. N. Dixit et coll. Monatsch. Chem., 94, 414-18 1963 EXAMPLE IV
  • a mixture of 7-chloro-3-acetylphenthiazine (49 g.), flowers of sulphur (9.3 g.) and morpholine (75 cc.) is heated under reflux for 16 hours.
  • the major proportion of the morpholine is then distilled ofl under a pressure of 20 mm. Hg, and ethanol (200 cc.) is added to the residue.
  • the 7-chloro-3-acetylphenthiazine used as starting material is prepared by reacting 5 N hydrochloric acid (190 cc.) with 7-ch1oro-3,IO-diacetylphenthiazine (62 g.) in ethanol (750 cc.) under reflux for 3 hours.
  • the product which crystallises is separated by filtration and washed with ethanol (20 cc.), diethyl ether (60 cc.) and petroleum ether (100 cc.), and dried.
  • Z-chloro-lO-acetylphenthiazine can be prepared by the method described by H. L. Yale, J. Amer. Chem. Soc. 77, 2270 (1955).
  • EXAMPLE V A mixture of 3-acetyl-7-methoxyphenthiazine (16.26 g.), sulphur (3.072 g.) and morpholine (36 cc.) is heated under reflux for 16 hours. The reaction mixture is then poured into ethanol (200 cc.). The crystals produced are separated by filtration and washed with ethanol (20 cc.) and hexane (50 cc.) to give (7-methoxy-3-phenthiazinyl)- acetothiomorpholide (14.4 g.) melting at 132.
  • a mixture of (7-methoxy-3-phenthiazinyl)acetothiomorpholide (14.4 g.), potassium hydroxide (23 g.) and ethanol (200 cc.) is heated under reflux for 21 hours.
  • the crystalline product formed is separated by filtration, washed with ethanol (10 cc.) and diethyl ether (30 cc.) to give a product (13.2 g.), the melting point of which is greater than 300.
  • This product is dissolved in water cc.), acidified with N hydrochloric acid (50' cc.) and the crystalline product formed is extracted with ethyl acetate (1200 cc.).
  • 3-acetyl-7-methoxyphenthiazine can be prepared as described in Example II.
  • Methyl ethyl methyl(3-phenthiazinyl)malonate (18.5 g.) is dissolved in ethanol (200 cc.) and the solution obtained is heated under reflux. N sodium hydroxide solution (134 cc.) is then introduced slowly, over a period of 1 /2 hours, and heating under reflux is continued for about another 2 hours. The alcohol is distilled ofl under a pressure of 20 mm. Hg, and the residue obtained is diluted with water (100 cc.). 4 N hydrochloric acid (45 cc.) is added and a product precipitates.
  • methyl ethyl methyl(3-phenthiazinyl)malonate employed as starting material is prepared in the following manner:
  • Methyl ethyl (3-phenthiazinyl)malonate (27.5 g.) and a solution of methyl iodide (13.6 g.) in anhydrous ethanol (40 cc.) is added to a solution of sodium (2.2 g.) in anhydrous ethanol (220 cc.).
  • the reaction mixture is heated at 55 for about 1 hour, then the ethanol is evaporated under a pressure of mm. Hg and the residue taken up with diethyl ether (350 cc.) and water (250 cc.).
  • the organic phase is decanted and washed with water (300 cc.).
  • the organic solution is treated with decolorising charcoal (3 g.), filtered and dried over anhydrous sodium sulphate.
  • Methyl ethyl (3-phenthiazinyl)malonate is prepared by reacting methyl (3-phenthiazinyl)acetate (30 g.) with ethyl carbonate (87 g.) in anhydrous ethanol (60 cc.) in the presence of sodium (2.7 g.). The mixture is heated at about 12l-124 for about 1 /2 hours while the alcohol formed is slowly distilled off. The reaction mixture is left to cool and N hydrochloric acid (117 cc.) is then added. The product crystallises and is separated by filtration and recrystallised from ethanol (230 cc.) to yield methyl ethyl (3-phenthiazinyl)malonate (18.6 g.) melting at 125.
  • Methyl ethyl (3-phenthiazinyl)malonate can also be obtained by the decarboxylation of ethyl 3-(3-phenthiazinyl)-3-methoxycarbonyl-2-oxopropionate (79 g.) by heating at about 180 under a pressure of 0.4 mm. Hg.
  • the residue obtained is purified by filtering a solution of it in benzene (200 cc.) through a column of alumina (1200 g.). After elution with benzene (11 litres) and evaporation of the solvent, there is obtained a paste which is crystallised from ethanol (80 cc.). The crystals are filtered off to yield methyl ethyl (3-phenthiazinyl)malonate (15 g.) melting at about 120.
  • Ethyl 3-(3-phenthiazinyl) 3 methoxycarbonyl-Z-oxopropionate is obtained by reacting methyl (3-phenthiazinyl)acetate (54.2 g.) with ethyl oxalate (29.2 g.) in anhydrous ethanol (100 cc.) in the presence of sodium (4.6 g.). The reaction mixture is left overnight at ambient temperature and then the alcohol is evaporated off under a pressure of 20 mm. Hg and the residue taken up in N hydrochloric acid (200 cc.) and diethyl ether (350 cc.) The organic phase is separated and washed with water (450 cc.).
  • Methyl (3-phenthiazinyl)acetate is prepared according to S. P. Massie, I. Cooke and W. A. Hills, J. Org. Chem., 21, 1006 (1956).
  • Methyl ethyl methyl(10-methyl-3-phenthiazinyl)malonate is prepared in the following way:
  • Methyl ethyl (l0-methyl-3-phenthiazinyl)malonate (27 g.) followed by a solution of methyl iodide (12.9 g.) in anhydrous ethanol (40 cc.) is added to a solution of sodium (2.09 g.) in anhydrous ethanol (220 cc.).
  • the reaction mixture is heated at 50 for 4 hours, and the ethanol then evaporated under a pressure of 20 mm. Hg.
  • the residue is taken up in water cc.) and methylene chloride (300 cc.), the organic solution decanted, washed with water (200 cc.) and dried over anhydrous sodium sulphate.
  • Methyl ethyl (10-methyl-3-phenthiazinyl)malonate is obtained by reacting methyl (10-methyl-3-phenthiazinyl) acetate (25 g.) with ethyl carbonate (73 g.) in anhydrous ethanol (50 cc.) in the presence of sodium (2.05 g.). The reaction mixture is heated at about l15 while the alcohol formed is slowly distilled off. The mixture is left to cool and then N hydrochloric acid (90 cc.) is added followed by methylene chloride (400 cc.). The organic phase is decanted, washed with water 100 cc.) and dried over anhydrous sodium sulphate.
  • the reaction mixture is left to cool and methylene chloride (250 cc.) then added.
  • the organic phase is decanted, washed with a saturated aqueous solution of sodium bicarbonate (100 cc.) and water (100 cc.) and then dried over anhydrous sodium sulphate. After evaporation of the solvent, a crystalline residue is obtained which is triturated in the cold with cyclohexane (50 cc.).
  • the crystals are separated by filtration and washed with petroleum ether 50 cc.) to yield methyl (lO-rnethyl-B-phenthiazinyl)acetate (25.6 g.) melting at 100-101.
  • Methyl ethyl ethyl( IO-methyl 3 phenthiazinyl)malonate (30.3 g.) is dissolved in ethanol (340 cc.) and the solution is heated under reflux. N sodium hydroxide solution (157 cc.) is introduced slowly over a period of 4 hours, and the reaction mixture maintained under reflux for a further one hour. After cooling, the solvents are distilled ofl under a pressure of 20 mm. Hg and the residue treated with N hydrochloric acid cc.) and then methylene chloride (250 cc.). The organic phase is decanted, washed with distilled water (210 cc.) and dried over anhydrous sodium sulphate.
  • methyl ethyl ethyl(10-methyl-3-phenthiazinyl)- malonate is prepared in the following way:
  • the organic solution is washed with water (200 cc.), treated with decolorising charcoal (10 g.), dried over anhydrous sodium sulphate and concentrated to dryness under reduced pressure (20 mm. Hg).
  • the oil obtained (48 g.) is dissolved in N sodium hydroxide solution (200 cc.) and the aqueous solution washed with diethyl ether (300 cc.), treated with decolorising charcoal (5 g.) and acidified with N hydrochloric acid (200 cc.).
  • the oil formed is dissolved in methylene chloride (350 cc.), the solution washed with water (100 cc.), treated with decolorising charcoal (5 g.) and dried over anhyd rous sodium sulphate.
  • methyl ethyl methyl(7-methoxy-10-methyl-3-phenthiazinyl)malonate employed as starting material is prepared in the following way:
  • Methyl ethyl (7-methoxy-10-methy1-3-phenthiazinyl) malonate (62.2 g.) followed by methyl iodide (45.7 g.) is added to a solution of sodium (4.45 g.) in an hydrous ethanol (500 cc.).
  • the reaction mixture is heated under reflux for 1 hour at 45", then for 6 hours at 55, and finally concentrated to dryness under reduced pressure (20 mm. Hg).
  • the residue is taken up in methylene chloride (300 cc.) and water (250 cc.), filtered in the presence of a filtration adjuvant, washed with methylene chloride (150 cc.) and water (150 cc.), and decanted.
  • aqueous solution is extracted once again with methylene chloride (100 cc.), and the combined organic solutions washed with water (100 cc.), aqueous 0.1 N sodium hyposulphite solution (200 cc.) and finally with water (200 cc.).
  • water 100 cc.
  • aqueous 0.1 N sodium hyposulphite solution 200 cc.
  • water 200 cc.
  • an oil (64.8 g.) which is dissolved in methylene chloride (100 cc.) and chromatographed over alumina (650 g.).
  • a fraction of 2.5 litres is recovered and concentrated to dryness under reduced pressure (20 mm. Hg) to give methyl ethyl methyl(7-methoxy 10 methyl-3 phenthiazinyl)malonate (59.7 g.) melting at 70-72.
  • Methyl ethyl (Z-methoxy-10-methyl-3-phenthiazinyl) malonate is prepared by reacting a solution of sodium (4.37 g.) in anhydrous ethanol (110 cc.) with a solution of methyl (7-methoxy-10-methyl-3-phenthiazinyl)acetate (59 g.) in ethyl carbonate (180 cc.). The reaction mixture is heated at about 105-1l0 for 3 hours and the ethanol formed is distilled oil as it is formed. The reaction mixture is acidified with N hydrochloric acid (200 cc.) and the oil formed is extracted with methylene chloride (200 cc.).
  • the methylene chloride solution is washed with water (210 cc.), treated with decolorising charcoal (5 g.), dried over anhydrous sodium sulphate and concentrated to dryness under reduced pressure (20 mm. Hg) giving an oil (77 g.) which is crystallised from methanol (300 cc.) to yield methyl ethyl (7-methoxy-10-methyl-3phenthiazinyl) malonate (62.4 g.) melting at 80-82.
  • Methyl (7-methoxy-10-methyI-B-phenthiazinyl)acetate is prepared by heating a mixture of (7-methoxy-l0-methyl- 3-phenthiazinyl)acetic acid (66.2 g.), methanol (26.5 cc.), 1,2-dichloroethane (66 cc.) and methanesulphonic acid (3.3 cc.) under reflux for 2 hours.
  • the reaction mixture is taken up in methylene chloride (200 cc.), filtered in the presence of filtration adjuvant and decanted.
  • the organic solution is washed with Water (100 cc.), followed by a saturated aqueous solution of potassium carbonate (300 cc.) and finally with water (200 cc.), treated with decolorising charcoal (5 g.), dried over anhydrous sodium sulphate and filtered and diluted to a volume of 500 cc.
  • the solution obtained is chromatographed over alumina (700 g.), eluted with methylene chloride and a fraction of 4 litres in volume recovered. Evaporation of this fraction to dryness under reduced pressure (20 mm.
  • EXAMPLE X A mixture of methyl (l0 methyl-3-phenthiazinyl)acetate (4.7 g.), ethanol (50 cc.) and N sodium hydroxide solution (20 cc.) is heated under reflux for 2 hours. The alcohol formed is evaporated under reduced pressure (2 0 mm. Hg) and the residue diluted with water (50 cc.). N hydrochloric acid (25 cc.) is added. The product precipitated is extracted with methylene chloride (200 cc.) and the organic solution dried over anhydrous sodium sulphate and evaporated. The crystalline residue obtained (4.5 g.), melting at about 128, is recrystallised from benzene (12 cc.) to yield (IO-methyl-3-phenthiazinyl)acetic acid (2.5 g.) melting at 138.
  • the methyl (10-methyl-3-phenthiazinyl)acetate employed as starting material is prepared by reacting methyl iodide (11.3 g.) with methyl (3-phenthiazinyl)acetate (5.4 g.) in anhydrous methanol (25 cc.) in a sealed tube at 125 for 23 hours. The reaction mixture is then diluted with methylene chloride (50 cc.). The organic solution is washed with N sodium hydrosulphite solution (20 cc.), a saturated sodium bicarbonate solution (6 cc.) and Water (20 cc.), dried over anhydrous sodium sulphate and evaporated to give methyl (10-methyl-3-phenthiazinyl) acetate (4.7 g.).
  • Methyl (3-phenthiazinyl)acetate is prepared according to S. -P. Massie et 0011., J. Org. Chem, 21, 1006 (1956 EXAMPLE XI
  • a mixture of (10-methyl-3-phenthiazinyl)acetonitrile (8 g.), potassium hydroxide (8.9 g.), water (1 cc.) and ethanol ('60 cc.) is heated under reflux for 7 hours. After cooling and dilution with water cc.), the solution obtained is treated with decolorising charcoal (0.8 g.), filtered and the filtrate acidified with 4 N hydrochloric acid (37 cc.). The crystals produced are separated by filtration, washed with water (40 cc.) and dried to give (10-rnethyl-3-phenthiazinyl)acetic acid (8.5 g.) melting at 143.
  • the (10-methyl-3-phenthiazinyl)acetonitrile employed 15 as starting material is prepared by reacting sodium cyanide with 3 bromomethyl-l-methylphenthiazine in aqueous acetone.
  • 3-bromomethyl-10-methyl-phenthiazine can be prepared by the action of phosphorus tribromide on 3-hydroxymethyl-IO-methylphenthiazine in the presence of pyridine in anhydrous diethyl ether.
  • Crystallisation is initiated by scratching the walls of the vessel and the reaction mixture is left to cool slowly. The crystals formed are separated by filtration giving a product (13.6 g.) melting at 77. Recrystallisation from a mixture of benzene-cyclohexane (1/ 1; 97 cc.) yields 3-hydroxymethyl-IO-methylphenthiazine (11.7 g.) melting at 7879.
  • 10-methyl-3-methoxycarbonyl-phenthiazine can be prepared according to the method described by G. Cauquil and A. Casadevall, Bull. Soc. Chim., p. 768 (1955).
  • the present invention includes within its scope pharmaceutical compositions containing, as active ingredient, at least one of the phenthiazine derivatives of Formula I, or pharmaceutically-acceptable salt thereof, in association with a pharmaceutical carrier or coating.
  • the invention includes especially such preparations made up for oral, parenteral or rectal administration, or topical application, e.g. as ointments or creams.
  • Solid compositions for oral administration include tablets, pills, powders, and granules.
  • the active compound is admixed with at least one inert diluent such as sucrose, lactose or starch.
  • the compositions may also comprise, as is normal practice, additional substances other than inert diluents, e.g. lubricating agents, such as magnesium stearate.
  • Liquid compositions for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water and liquid paraffin.
  • such compositions may also comprise adjuvants, such as wetting, emulsifying and suspending agents, and
  • compositions according to the invention for oral administration, also include capsules of absorbable material such as gelatin containing the active substance with or without the addition of diluents or excipients.
  • Preparations according to the invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions.
  • nonaqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil, and injectable organic esters such as ethyl oleate.
  • These compositions may also contain adjuvants such as preserving, wetting, emulsifying and dispersing agents. They may be sterilised by, for example, filtration through a bacteriaretaining filter, by incorporation in the compositions of sterilising agents, by irradiation, or by heating. They may also be manufactured in the form of sterile solid compositions, 'which can be dissolved in sterile water or some other sterile injectable medium immediately before use.
  • compositions for rectal administration are suppositories which may contain, in addition to the active substance, excipients such as cacao butter or a suitable wax base.
  • the percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained.
  • the dosage depends on the desired therapeutic effect, on the route of administration and on the duration of the treatment.
  • the dosages are generally between 10 and mg. per kilogramme of animal weight.
  • Example XIV Tablets analogous to those of Example XII may be prepared by replacing the (10-methyl-3-phenthiazinyl)- acetic acid by the same weight of (7-methoxy-l0-methyl- 3-phenthiazinyl) acetic acid.
  • Example XVII Tablets analogous to those of Example XV may be prepared by replacing the 2-(7-methoxy-lO-methyl-3- phenthiazinyl)propionic acid by the same weight of 2- (10-methyl-3-phenthiazinyl)propionic acid.
  • a phenthiazine selected from the group consisting of a compound of the formula:
  • R is a member selected from the group consisting of methyl and, when R is a member selected from the group consisting of methyl and ethyl, hydrogen and Y is a member selected from the group consisting of hydrogen and chlorine.
  • R is a member selected from the group consisting of hydrogen and methyl
  • R is a member selected from the group consisting of hydrogen, methyl and ethyl
  • Y is a member selected from the group consisting of methyl and methoxy.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US505428A 1964-10-29 1965-10-25 Phenthiazine derivatives Expired - Lifetime US3450698A (en)

Applications Claiming Priority (9)

Application Number Priority Date Filing Date Title
FR993221A FR1501710A (fr) 1964-10-29 1964-10-29 Nouveaux produits dérivés de la phénothiazine et leur préparation
FR993222A FR1502614A (fr) 1964-10-29 1964-10-29 Nouveaux dérivés de la phénothiazine et leur préparation
FR993385A FR1501711A (fr) 1964-10-29 1964-10-30 Nouveaux dérivés de la phénothiazine et leur procédé de préparation
FR101A FR91551E (fr) 1964-10-29 1964-12-28 Nouveaux produits dérivés de la phénothiazine et leur préparation
FR32594A FR90403E (fr) 1964-10-29 1965-09-24 Nouveaux dérivés de la phénothiazine et leur préparation
FR32596A FR90404E (fr) 1964-10-29 1965-09-24 Nouveaux dérivés de la phénothiazine et leur procédé de préparation
FR32595A FR92113E (fr) 1964-10-29 1965-09-24 Nouveaux produits dérivés de la phénothiazine et leur préparation
US50542865A 1965-10-25 1965-10-25
DER0041864 1965-10-29

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CH (3) CH465615A (enrdf_load_stackoverflow)
CY (1) CY525A (enrdf_load_stackoverflow)
DK (1) DK120900B (enrdf_load_stackoverflow)
FI (1) FI45450C (enrdf_load_stackoverflow)
FR (11) FR1502614A (enrdf_load_stackoverflow)
GB (1) GB1048680A (enrdf_load_stackoverflow)
IL (1) IL24537A (enrdf_load_stackoverflow)
IS (1) IS696B6 (enrdf_load_stackoverflow)
MY (1) MY7000053A (enrdf_load_stackoverflow)
NL (1) NL138935B (enrdf_load_stackoverflow)
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3927093A (en) * 1972-10-10 1975-12-16 Squibb & Sons Inc 2-(O-aminophenylthio)benzyl alcohols
US4666907A (en) * 1983-10-05 1987-05-19 Merck Frosst Canada, Inc. Phenothiazine and derivatives and analogs and use as leukotriene biosynthesis inhibitors
US4845083A (en) * 1983-10-05 1989-07-04 Merck Frosst Canada, Inc. Method of inhibiting mammalian leukotriene biosynthesis

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0068563A3 (en) * 1981-06-23 1983-06-15 THE PROCTER & GAMBLE COMPANY Heterocyclic acetic acid compounds and compositions for treating bone diseases

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3927093A (en) * 1972-10-10 1975-12-16 Squibb & Sons Inc 2-(O-aminophenylthio)benzyl alcohols
US4666907A (en) * 1983-10-05 1987-05-19 Merck Frosst Canada, Inc. Phenothiazine and derivatives and analogs and use as leukotriene biosynthesis inhibitors
US4845083A (en) * 1983-10-05 1989-07-04 Merck Frosst Canada, Inc. Method of inhibiting mammalian leukotriene biosynthesis

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FR1502614A (fr) 1967-11-24
CH457445A (fr) 1968-06-15
CY525A (en) 1970-02-12
CH465615A (fr) 1968-11-30
SE322517B (enrdf_load_stackoverflow) 1970-04-13
BE671573A (enrdf_load_stackoverflow) 1966-04-28
FR4164M (enrdf_load_stackoverflow) 1966-05-16
IS1516A7 (is) 1966-04-30
FR91551E (fr) 1968-07-05
MY7000053A (en) 1970-12-31
FR92113E (fr) 1968-09-27
FR1501711A (fr) 1967-11-18
NL6513997A (enrdf_load_stackoverflow) 1966-05-02
NL138935B (nl) 1973-05-15
DE1620170B2 (de) 1975-07-17
FR90403E (fr) 1967-12-08
FR1501710A (fr) 1967-11-18
BR6574391D0 (pt) 1973-08-09
CH454867A (fr) 1968-04-30
FR4163M (enrdf_load_stackoverflow) 1966-05-16
FR4276M (enrdf_load_stackoverflow) 1966-07-11
FI45450B (enrdf_load_stackoverflow) 1972-02-29
FR149F (enrdf_load_stackoverflow)
FR90404E (fr) 1967-12-08
IL24537A (en) 1969-05-28
FI45450C (fi) 1972-06-12
OA02036A (fr) 1970-05-05
IS696B6 (is) 1970-02-13
DE1620170A1 (de) 1970-05-21
DK120900B (da) 1971-08-02
NO120733B (enrdf_load_stackoverflow) 1970-11-30
GB1048680A (en) 1966-11-16

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